Project description:Human induced pluripotent stem cells (iPS cells) resemble embryonic stem cells and can differentiate into cell derivatives of all three germ layers. However, frequently the differentiation efficiency of iPS cells into some lineages is rather poor. Here, we found that fusion of iPS cells with human hematopoietic stem cells (HSC) enhances iPS cell differentiation. Such iPS hybrids showed a prominent differentiation bias towards hematopoietic lineages but also towards other mesendodermal lineages. Additionally, during differentiation of iPS hybrids expression of early mesendodermal markers - Brachyury (T), MIX1 Homeobox-Like Protein 1 (MIXL1) and Goosecoid (GSC) - appeared with faster kinetics than in parental iPS cells. Following iPS hybrid differentiation there was a prominent induction of NODAL and inhibition of NODAL signaling blunted mesendodermal differentiation. This indicates that NODAL signaling is critically involved in mesendodermal bias of iPS hybrid differentiation. In summary, we demonstrate that iPS cell fusion with HSC prominently enhances iPS differentiation. 11 samples were hybridized GeneChip Human Gene 1.0 ST Arrays (Affymetrix)
Project description:Surface topography impacts on cell growth and differentiation, but it is not trivial to generate defined surface structures and to assess the relevance of specific topographic parameters. In this study, we have systematically compared in vitro differentiation of mesenchymal stem cells (MSCs) on a variety of groove/ridge structures. Micro- and nano-patterns were generated in polyimide using reactive ion etching or multi beam laser interference, respectively. These structures affected cell spreading and orientation of human MSCs, which was also reflected in focal adhesions morphology and size. Time-lapse demonstrated directed migration parallel to the nano-patterns. Overall, surface patterns clearly enhanced differentiation of MSCs towards specific lineages: 15 um ridges increased adipogenic differentiation whereas 2 um ridges enhanced osteogenic differentiation. Notably, nano-patterns with a periodicity of 650 nm increased differentiation towards both osteogenic and adipogenic lineages. However, in absence of differentiation media surface structures did neither induce differentiation, nor lineage-specific gene expression changes. Furthermore, nanostructures did not affect the YAP/TAZ complex, which is activated by substrate stiffness. Our results provide further insight into how structuring of tailored biomaterials and implant interfaces - e.g. by multi beam laser interference in sub-micrometer scale - do not induce differentiation of MSCs per se, but support their directed differentiation.
Project description:Surface topography impacts on cell growth and differentiation, but it is not trivial to generate homogeneous surface structures and to define the specific morphological parameters of relevance. In this study, we have compared gene expression profiles of mesenchymal stem cells (MSCs) on nanostructured groove/ridge surfaces. Patterns were generated in polyimide using multi beam laser interference. These structures affected cell size and orientation of human MSCs. Furthermore, the nano-patterns with a periodicity of 650 nm increased differentiation towards osteogenic and adipogenic lineages. However, in absence of differentiation media the surface structures did neither induce differentiation, nor lineage-specific gene expression changes – as assessed by genome wide gene expression profiles with Affymetrix microarray technology. Our results demonstrate that grooves and ridges at a periodicity of 650 nm enhance the propensity of MSCs to differentiate towards adipogenic and/or osteogenic lineages – but they do not directly govern lineage-specific gene expression changes. 9 samples were hybridized to the GeneChip Human Gene 2.0 ST Array (Affymetrix). In comparison to the manuscript the donor IDs refer as follows: donor 1 = AT57; donor 2 = AT58; donor 3 = AT61.
Project description:Surface topography impacts on cell growth and differentiation, but it is not trivial to generate homogeneous surface structures and to define the specific morphological parameters of relevance. In this study, we have compared gene expression profiles of mesenchymal stem cells (MSCs) on nanostructured groove/ridge surfaces. Patterns were generated in polyimide using multi beam laser interference. These structures affected cell size and orientation of human MSCs. Furthermore, the nano-patterns with a periodicity of 650 nm increased differentiation towards osteogenic and adipogenic lineages. However, in absence of differentiation media the surface structures did neither induce differentiation, nor lineage-specific gene expression changes – as assessed by genome wide gene expression profiles with Affymetrix microarray technology. Our results demonstrate that grooves and ridges at a periodicity of 650 nm enhance the propensity of MSCs to differentiate towards adipogenic and/or osteogenic lineages – but they do not directly govern lineage-specific gene expression changes.
Project description:The cellular microenvironment shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and benefit from hypoxic culture in vitro. Yet, how different components of the hypoxia response impact stem cell transcriptional networks and lineage choices remains unclear. Here we investigated the effect of acute and prolonged hypoxia on stem cell states and differentiation efficiencies of embryonic and extraembryonic cells. We show that prolonged hypoxia enhances differentiation of embryonic stem (ES) cells towards the mesendoderm lineage by transcriptionally priming cells with a primitive streak signature including Wnt3 and T expression. Exposure to hypoxia in ES culture or during formation of gastrulation-mimicking organoids (gastruloids) moderates T expression and enhances structural complexity. Hypoxic gastruloids generated without exogenous Wnt induction can spontaneously elongate and self-organize. Direct gene regulation by Hif1a, combined with DNA demethylation and metabolic rewiring modulate the transcriptional response and phenotypic outcome. Our findings highlight the influence of the microenvironment on stem cell function and provide a rationale supportive of applying physiological conditions in synthetic embryo models.
Project description:EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. EZH2 downregulation markedly enhances neuron differentiation of human mesenchymal stem cells (hMSCs)chromatin at promoters of EZH2 target genes. comparison of knockdown EZH2 of hMSCs vs hMSCs
Project description:Human induced pluripotent stem cells (iPS cells) resemble embryonic stem cells and can differentiate into cell derivatives of all three germ layers. However, frequently the differentiation efficiency of iPS cells into some lineages is rather poor. Here, we found that fusion of iPS cells with human hematopoietic stem cells (HSC) enhances iPS cell differentiation. Such iPS hybrids showed a prominent differentiation bias towards hematopoietic lineages but also towards other mesendodermal lineages. Additionally, during differentiation of iPS hybrids expression of early mesendodermal markers - Brachyury (T), MIX1 Homeobox-Like Protein 1 (MIXL1) and Goosecoid (GSC) - appeared with faster kinetics than in parental iPS cells. Following iPS hybrid differentiation there was a prominent induction of NODAL and inhibition of NODAL signaling blunted mesendodermal differentiation. This indicates that NODAL signaling is critically involved in mesendodermal bias of iPS hybrid differentiation. In summary, we demonstrate that iPS cell fusion with HSC prominently enhances iPS differentiation.
Project description:EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. EZH2 downregulation markedly enhances neuron differentiation of human mesenchymal stem cells (hMSCs)chromatin at promoters of EZH2 target genes.
Project description:Schittler2010 - Cell fate of progenitor cells, osteoblasts or chondrocytes
Mathematical model describing the mechanism of differentiation of mesenchymal stem cells to bone (osteoblasts) or cartilage (chondrocytes) cells.
This model is described in the article:
Cell differentiation modeled via a coupled two-switch regulatory network.
Schittler D, Hasenauer J, Allgöwer F, Waldherr S.
Chaos 2010 Dec; 20(4): 045121
Abstract:
Mesenchymal stem cells can give rise to bone and other tissue cells, but their differentiation still escapes full control. In this paper we address this issue by mathematical modeling. We present a model for a genetic switch determining the cell fate of progenitor cells which can differentiate into osteoblasts (bone cells) or chondrocytes (cartilage cells). The model consists of two switch mechanisms and reproduces the experimentally observed three stable equilibrium states: a progenitor, an osteogenic, and a chondrogenic state. Conventionally, the loss of an intermediate (progenitor) state and the entailed attraction to one of two opposite (differentiated) states is modeled as a result of changing parameters. In our model in contrast, we achieve this by distributing the differentiation process to two functional switch parts acting in concert: one triggering differentiation and the other determining cell fate. Via stability and bifurcation analysis, we investigate the effects of biochemical stimuli associated with different system inputs. We employ our model to generate differentiation scenarios on the single cell as well as on the cell population level. The single cell scenarios allow to reconstruct the switching upon extrinsic signals, whereas the cell population scenarios provide a framework to identify the impact of intrinsic properties and the limiting factors for successful differentiation.
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